Conformational changes relevant to channel activity and folding within the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator.

Deletion of Phe-508 (F508del) in the first nucleotide binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) leads to defects in folding and channel gating. NMR data on human F508del NBD1 indicate that an H620Q mutant, shown to increase channel open probability, and the dual corrector/potentiator CFFT-001 similarly disrupt interactions between ß-strands S3, S9, and S10 and the C-terminal helices H8 and H9, shifting a preexisting conformational equilibrium from helix to coil. CFFT-001 appears to interact with ß-strands S3/S9/S10, consistent with docking simulations. Decreases in T(m) from differential scanning calorimetry with H620Q or CFFT-001 suggest direct compound binding to a less thermostable state of NBD1. We hypothesize that, in full-length CFTR, shifting the conformational equilibrium to reduce H8/H9 interactions with the uniquely conserved strands S9/S10 facilitates release of the regulatory region from the NBD dimerization interface to promote dimerization and thereby increase channel open probability. These studies enabled by our NMR assignments for F508del NBD1 provide a window into the conformational fluctuations within CFTR that may regulate function and contribute to folding energetics.

[Acute superior mesenteric ischemia: a contrast study on short-and mid-term result between stent implantation and pharmaceutical thrombolysis].

OBJECTIVE: To compare the short-term and medium-term result of stent implantation with pharmaceutical thrombolysis in patients with acute superior mesenteric artery occlusion. METHODS: From January, 2004 to December, 2008, thirty-five patients diagnosed acute superior mesenteric ischemia, 12 patients treated with stent implantation (interventional therapy group) and 23 patients with pharmaceutical thrombolysis (thrombolytic therapy group). Interventional therapy group treated with balloon dilatation and stent implantation assisted with anticoagulation, antiplatelet and vascular dilation agents. Thrombolytic therapy group used urokinase combined with anticoagulation, antiplatelet and vascular dilation agents. All patients had taken clopidogrel and aspirin orally after discharged and followed up. The clinical effects of both groups were evaluated separately and the Fisher exact test was used to analysis the significant differences. RESULTS: In the 23 cases of thrombolytic therapy group, 7 cases was effective, 16 cases was ineffective (7 cases aggravated or died, 9 cases turn to surgical operation). In the 12 cases of interventional therapy group, 10 cases treated with stent implantation (1 case died of acute cardiac infarction 3 days after interventional operation), 2 cases failed in recanalizing. All patients were followed up after discharged (range 1 - 48 months, mean 15 ± 12 months), 1 case in thrombolytic therapy group was stable, 6 cases died of the recurrence of acute superior mesenteric artery occlusion; 7 cases in interventional therapy group was stable, 1 case died of acute cardiac infarction 20 months after interventional operation (intestinal ischemia not appeared), 1 case had intestinal ischemia reoccurred and recovered by superior mesenteric artery thrombolysis. CONCLUSIONS: In the treatment of acute superior mesenteric ischemia, stent implantation was obviously superior to pharmaceutical thrombolysis in improving intestinal ischemia and survival, therefore it could provided a reliable choice for the patients who had not appeared intestinal necrosis.